The present invention relates to new dihydropyridine derivatives and the use of the dihydropyridine derivatives as medicines. The activation of N-type calcium channel is concerned with various diseases, for example, acute stage of ischemic cerebrovascular disorders caused by cerebral infarction or intracerebral bleeding (including subarachnoidal hemorrhage); progressive neurodegenerative diseases such as Alzheimer""s disease, AIDS related dementia and Parkinson""s disease, dementia due to cerebrovascular disorder and ALS; neuropathy caused by head injury; various pains such as pain caused by spinal injury, diabetes or thromboangiitis obliterans, postoperative pain, migraine and visceral pain; various diseases associated with psychogenic stress such as bronchial asthma, unstable angina and irritable colitis; emotional disorder and withdrawal symptoms after addiction to drugs such as ethanol addiction withdrawal symptoms. The compounds of the present invention can inhibit the activation of the N-type calcium channel and, therefore usable as therapeutic agents for these diseases.
Calcium channels are now classified into subtypes of L, N, P, Q, R and T. Each subtype of calcium channels is organ-specifically distributed. It is known that particularly N-type calcium channel is widely distributed in pars centralis, peripheral nerves and adrenomedullary cells and participates in neuronal cell death, regulation of blood catecholamine level and control of senses such as perception.
It has been confirmed that omega conotoxin GVIA and omega conotoxin MVIIA, which are peptides selectively inhibiting N-type calcium channel, inhibit the release of excitatory neurotransmitters in the sliced brain preparation. It is also confirmed in animal experiments that they inhibit the progress of neuronal necrosis associated with cerebrovascular disorders. It is generally considered that compounds having a N-type calcium channel blocking action are clinically effective in the treatment of acute stage of ischemic cerebrovascular disorders caused by cerebral infarction or intracerebral bleeding (including subarachnoidal hemorrhage); progressive neurodegenerative diseases such as Alzheimer""s disease, AIDS related dementia and Parkinson""s disease, dementia due to cerebrovascular disorder and ALS; and neuropathy caused by head injury. Further, it is confirmed in animal tests that omega conotoxin MVIIA relieves a pain induced by formaldehyde, hot plate and peripheral neuropathy. Accordingly, omega conotoxin MVIIA is considered to be clinically effective against various pains such as pain caused by spinal injury, diabetes or thromboangiitis obliterans, postoperative pain, migraine and visceral pain. In addition, because omega conotoxin GVIA inhibits the release of catecholamine from cultured sympathetic ganglion cells, catecholamine secretion from canine adrenal medulla and the contraction of the isolated blood vessel by electric stimulation of the perivascular nerve, it is considered that compounds having N-type calcium channel-blocking effects are clinically effective against various diseases related to psychogenic stress such as bronchial asthma, unstable angina and irritable colitis [Neuropharmacol., 32, 1141 (1993)].
Some peptidergic and non-peptidergic compounds which selectively affect N-type calcium channels have been ever disclosed (see, for example, WO 9313128 and WO 9849144). However, none of them was actually used as a medicine. Some of the compounds which affect N-type calcium channels are also effective against various types of calcium channels of other than N-type [British Journal of Pharmacology, 122 (1) 37-42, 1997]. For example, compounds having an antagonistic effect on L-type calcium channels which are very closely related to hypotensive effect, could not be used for diseases for which N-type antagonists will be used (such as cerebral stroke, neuralgia, terminal cancer pain and pain of spinal injury). Under these circumstances, the development of a highly active antagonist selective toward N-type calcium channel has been eagerly demanded.
The object of the present invention is to provide new compounds having a selective antagonistic effect on N-type calcium channels.
Another object of the present invention is to provide antagonists to N-type calcium channels.
Still another object of the present invention is to provide a therapeutic agent for any of acute stage of ischemic cerebrovascular disorders caused by cerebral infarction or intracerebral bleeding, Alzheimer""s disease, AIDS related dementia, Parkinson""s disease, progressive neurodegenerative diseases, neuropathy caused by head injury, pain caused by thromboangiitis obliterans, postoperative pain, migraine, visceral pain, bronchial asthma, unstable angina, irritable colitis and withdrawal symptoms after addiction to drugs.
A further object of the present invention is to provide a pharmaceutical composition.
After synthesizing various dihydropyridine derivatives and examining the N-type calcium channel inhibiting effect (determined by fluorescent dye method) and L-type calcium channel inhibiting effect of the newly synthesized compounds and well-known dihydropyridine derivatives for the purpose of solving the above-described problems, the inventors have found that specified, new dihydropyridine derivatives have an excellent effect of selectively antagonizing N-type calcium channels. The present invention has been completed on the basis of this finding. Namely, the present invention provides dihydropyridine derivatives of the following general formula (1) and pharmaceutically acceptable salts thereof. 
wherein
A represents a group of the following general formula (2), or 1-naphthyl, 2-naphthyl, thiophene-3-yl, thiophene-2-yl, furan-3-yl, furan-2-yl, pyridine-4-yl, pyridine-3-yl, pyridine-2-yl, indole-2-yl or indole-3-yl group: 
wherein R1, R2, R3, R4 and R5 may be the same or different from each other and each represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, amino group, cyano group, nitro group, a lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a lower alkoxycarbonyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an aryl group, a heteroaryl group, an aryl-lower alkoxyl group or an aroyl group,
B represents cyano group, nitro group, acetyl group, tetrazole group, triazole group or a group of the following general formula (3) or (4): 
wherein R6 to R8 each represent hydrogen atom, a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms, an alkyl group substituted with a cyclic alkyl group which may contain a hetero atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a hydroxy-lower alkyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkenyl group, an aryl-lower alkyl group, an aryl-lower alkenyl group, a heteroaryl-lower alkyl group (excluding pyridine-3-ylpropyl group), a heteroaryl-lower alkenyl group, a cyano-lower alkyl group or a cyano-lower alkenyl group, and the chains of R6 to R8 may contain a hetero atom, or R7 and R8 may together form a ring which may contain a hetero atom,
C represents hydrogen atom, a lower alkyl group, dimethoxymethyl group, cyano group, a hydroxy-lower alkyl group, a halogeno-lower alkyl group (C does not represent these groups listed above when E represents hydrogen atom, a lower alkyl group, dimethoxymethyl group, cyano group, a hydroxy-lower alkyl group or a halogeno-lower alkyl group), a substituted or unsubstituted amino-lower alkyl group (the substituent represents hydrogen atom or a lower alkyl group, and if necessary, they may contain a hetero atom in the chain thereof), an azido-lower alkyl group, an aryl group, a heteroaryl group, an aryl-lower alkyl group, a heteroaryl-lower alkyl group or a lower alkyl group substituted with a cyclic alkyl group which may contain a hetero atom in the group,
D represents hydrogen atom, a lower alkyl group, a hydroxy-lower alkyl group or an aryl-lower alkyl group,
E represents hydrogen atom, a lower alkyl group, dimethoxymethyl group, cyano group, a hydroxy-lower alkyl group, a halogeno-lower alkyl group (E does not represent these groups listed above when C represents hydrogen atom, a lower alkyl group, dihydropyridine group, cyano group, a hydroxy-lower alkyl group or a halogeno-lower alkyl group), a substituted or unsubstituted amino-lower alkyl group (the substituent represents hydrogen atom or a lower alkyl group, and if necessary, they may contain a hetero atom in the chain thereof), an azido-lower alkyl group, an aryl group, a heteroaryl group, an aryl-lower alkyl group, a heteroaryl-lower alkyl group or a lower alkyl group substituted with a cyclic alkyl group which may contain a hetero atom in the group,
F represents an aryl group, a heteroaryl group or a cyclic alkyl group which may contain a hetero atom in the group, excluding piperidinyl group and piperazinyl group,
G represents hydrogen atom or a lower alkyl group,
X1 represents an interatomic bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, and
Y represents a group represented by any of the following general formulae (5) to (14): 
xe2x80x83wherein R9 to R12, R and R0 may the same or different from each other, and they each represent hydrogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a thio-lower alkyl group, an alkylthio-lower alkyl group, an aryl group, an aryl-lower alkyl group or a heteroaryl-lower alkyl group,
B and C may together form a lactone ring or a lactam ring, two of R1 to R3 may be bonded together to form a ring, R9 and R10 may be bonded together to form a ring, and R0 may be condensed with F to form a ring.
The present invention also provides an N-type calcium channel antagonist containing a dihydropyridine derivative of above general formula (1-1) or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention further provides a therapeutic agent containing the dihydropyridine derivative represented by the following general formula (1-1) or a pharmaceutically acceptable salt thereof as the active ingredient, for any of acute stage of ischemic cerebrovascular disorders caused by cerebral infarction or intracerebral bleeding, Alzheimer""s disease, AIDS related dementia, Parkinson""s disease, progressive neurodegenerative diseases, neuropathy caused by head injury, pain caused by thromboangiitis obliterans, postoperative pain, migraine, visceral pain, bronchial asthma, unstable angina, irritable colitis and withdrawal symptoms after addiction to drugs: 
wherein
A represents a group of the following general formula (2), or 1-naphthyl, 2-naphthyl, thiophene-3-yl, thiophene-2-yl, furan-3-yl, furan-2-yl, pyridine-4-yl, pyridine-3-yl, pyridine-2-yl, indole-2-yl or indole-3-yl group: 
wherein R1, R2, R3, R4 and R5 may be the same or different from each other and each represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, amino group, cyano group, nitro group, a lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a lower alkoxycarbonyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an aryl group, a heteroaryl group, an aryl-lower alkoxyl group or an aroyl group,
B represents cyano group, nitro group, acetyl group, tetrazole group, triazole group or a group of the following general formula (3) or (4): 
wherein R6 to R8 each represent hydrogen atom, a linear, branched or cyclic, saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms, an alkyl group substituted with a cyclic alkyl group which may contain a hetero atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a hydroxy-lower alkyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkenyl group, an aryl-lower alkyl group, an aryl-lower alkenyl group, a heteroaryl-lower alkyl group (excluding pyridine-3-ylpropyl group), a heteroaryl-lower alkenyl group, a cyano-lower alkyl group or a cyano-lower alkenyl group, and the chains of R6 to R8 may contain a hetero atom, or R7 and R8 may together form a ring which may contain a hetero atom,
C represents hydrogen atom, a lower alkyl group, dimethoxymethyl group, cyano group, a hydroxy-lower alkyl group, a halogeno-lower alkyl group, an amino-lower alkyl group, an azido-lower alkyl group, an aryl group, a heteroaryl group, an aryl-lower alkyl group, a heteroaryl-lower alkyl group (C does not represent these groups listed above when E represents hydrogen atom, a lower alkyl group, dimethoxymethyl group, cyano group, a hydroxy-lower alkyl group, a halogeno-lower alkyl group, an amino-lower alkyl group, an azido-lower alkyl group, an aryl group, a heteroaryl group, an aryl-lower alkyl group or a heteroaryl-lower alkyl group), a monosubstituted amino-lower alkyl group wherein the substituent represents a lower alkyl group, a disubstituted amino-lower alkyl group wherein the substituents represent the same or different lower alkyl groups, or a lower alkyl group substituted with a cyclic alkyl group which may contain a hetero atom in the group,
D represents hydrogen atom, a lower alkyl group, a hydroxy-lower alkyl group or an aryl-lower alkyl group,
E represents hydrogen atom, a lower alkyl group, dimethoxymethyl group, cyano group, a hydroxy-lower alkyl group, a halogeno-lower alkyl group, an amino-lower alkyl group, an azido-lower alkyl group, an aryl group, a heteroaryl group, an aryl-lower alkyl group, a heteroaryl-lower alkyl group (E does not represent these groups listed above when C represents hydrogen atom, a lower alkyl group, dimethoxymethyl group, cyano group, a hydroxy-lower alkyl group, a halogeno-lower alkyl group, an amino-lower alkyl group, an azido-lower alkyl group, an aryl group, a heteroaryl group, an aryl-lower alkyl group or a heteroaryl-lower alkyl group), a monosubstituted amino-lower alkyl group wherein the substituent represents a lower alkyl group, a disubstituted amino-lower alkyl group wherein the substituents represent the same or different lower alkyl groups, or a lower alkyl group substituted with a cyclic alkyl group which may contain a hetero atom in the group,
F represents an aryl group, a heteroaryl group or a cyclic alkyl group which may contain a hetero atom in the group, excluding piperidinyl group and piperazinyl group,
G represents hydrogen atom or a lower alkyl group,
X1 represents an interatomic bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, and
Y represents a group represented by any of the following general formulae (5) to (14): 
xe2x80x83wherein R9 to R12, R and R0 may the same or different from each other, and they each represent hydrogen atom, a lower alkyl group, a hydroxy-lower alkyl group, a thio-lower alkyl group, an alkylthio-lower alkyl group, an aryl group, an aryl-lower alkyl group or a heteroaryl-lower alkyl group,
B and C may together form a lactone ring or a lactam ring, two of R1 to R3 may be bonded together to form a ring, R9 and R10 may be bonded together to form a ring, and R0 may be condensed with F to form a ring.
The present invention also provides a pharmaceutical composition containing the dihydropyridine derivative represented by the above general formula (1) or a pharmaceutically acceptable salt thereof, a carrier and/or a diluent.
The term xe2x80x9clowerxe2x80x9d herein indicates that the group has 1 to 6 carbon atoms. Alkyl groups themselves and also alkyl groups in alkoxyl groups, alkenyl groups, alkylamino groups, alkylthio groups and alkanoyl groups may be either linear or branched. Examples of these alkyl groups are methyl group, ethyl group, propyl group, isopropyl group, butyl group, secondary and tertiary butyl groups, pentyl group and hexyl group. Among them, those having 1 to 3 carbon atoms are preferred. The aryl-lower alkyl groups include, for example, benzyl group. The heteroaryl-lower alkyl groups include, for example, pyridylmethyl group. The aryl-lower alkoxyl groups include, for example, benzyloxy group. The halogen atoms include fluorine, chlorine, bromine and iodine atoms. In the present specification, the aryl groups are both substituted and unsubstituted aryl groups. They are preferably phenyl group and substituted phenyl group, and the substituents are particularly preferably halogens, alkyl groups and alkoxyl groups. The heteroaryl groups are substituted or unsubstituted heteroaryl groups such as, preferably, pyridyl group, furyl group, substituted pyridyl groups and substituted furyl groups. Halogens, alkyl groups and alkoxyl groups are particularly preferred as the substituents. The aroyl groups include, for example, benzoyl group and pyridylcarbonyl group.
In the present invention, the amino-lower alkyl groups indicate unsubstituted amino-lower alkyl groups, and the unsubstituted or substituted amino-lower alkyl groups indicate unsubstituted, monosubstituted or disubstituted amino-lower alkyl groups.
1-Naphthyl group, 2-naphthyl group, indole-2-yl group and indole-3-yl group represented by A in the above general formulae (1) and (1-1) are either unsubstituted or substituted. The substituents are those listed above for R1 to R5.
Thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group and pyridine-2-yl group represented by A are also either unsubstituted or substituted. When two or more substituents are contained therein, they may form a ring together. The substituents are those described above with reference to 1-naphthyl group or the like. The rings formed by those groups include benzothiophene, benzofuran, quinoline, isoquinoline, etc.
A is preferably a group represented by the general formula (2). In these groups, those wherein one or two of R1 to R5 represent a halogen atom, particularly chlorine atom are preferred. Particularly preferably, R4 represents chlorine atom, and R1 to R3 and R5 each represent hydrogen atom.
The substituents in the substituted or un-substituted aryl groups and substituted or un-substituted heteroaryl groups represented by R6 to R8 in the groups represented by general formula (3) or (4) in groups B in above general formulae (1) and (1-1) are, for example, halogen atoms (such as fluorine, chlorine, bromine and iodine atoms), hydroxyl group, carboxyl group, amino group, cyano group, nitro group, lower alkyl groups, lower alkoxyl groups, halogeno-lower alkyl groups and lower alkoxycarbonyl groups.
The groups represented by B are preferably carboxyl group, carbamoyl group which may have a substituent, cyano group and lower alkoxycarbonyl (such as methoxycarbonyl) groups. Carboxyl group and carbamoyl group which may have a substituent are more preferred.
The lower alkyl groups, hydroxy-lower alkyl groups, halogeno-lower alkyl groups, substituted or unsubstituted amino-lower alkyl groups, azido-lower alkyl groups, aryl groups, heteroaryl groups, aryl-lower alkyl groups, heteroaryl-lower alkyl groups and lower alkyl groups substituted with a cyclic alkyl group which may contain a hetero atom in the ring thereof may contain a hetero atom in their chains. The hetero atoms include, for example, oxygen, nitrogen and sulfur atoms. The groups containing such a hetero atom in the chain include, for example, hydroxyethoxymethyl group, methoxymethyl group, methoxyethyl group, chloroethoxymethyl group, aminoethoxymethyl group, monomethylaminoethoxymethyl group, dimethylaminoethoxymethyl group, azidoethoxymethyl group, methylthioethyl group, phenylethoxymethyl group, 2-pyridylethoxymethyl group, 3-pyridylethoxymethyl group, 4-pyridylethoxymethyl group, cyclohexylethoxymethyl group and piperidine-1-ylethoxymethyl group.
C and E in the general formula (1) are each preferably a lower alkyl group, a substituted or unsubstituted amino-lower alkyl group, an aryl-lower alkyl group, a heteroaryl-lower alkyl group or a lower alkyl group substituted with a cyclic alkyl group (containing or not containing a hetero atom in the ring), and they may contain a hetero atom in the chain thereof. More preferably, they are each an aryl-lower alkyl group or a lower alkyl group substituted with a cyclic alkyl group (containing or not containing a hetero atom in the ring), and they may contain a hetero atom in the chain thereof. Preferred examples of them include methyl group, methoxymethyl group, aminoethoxymethyl group, dimethylaminoethoxymethyl group, phenylethoxymethyl group, 2-pyridylethoxymethyl group, cyclohexylethoxymethyl group and piperidine-1-ylethoxymethyl group. Among them, methyl group, methoxymethyl group, aminoethoxymethyl group, phenylethoxymethyl group and cyclohexylethoxymethyl group are more preferred.
The lower alkyl groups, hydroxy-lower alkyl groups, halogeno-lower alkyl groups, amino-lower alkyl groups, azido-lower alkyl groups, aryl-lower alkyl groups, heteroaryl-lower alkyl groups, mono-substituted amino-lower alkyl groups, disubstituted amino-lower alkyl groups and lower alkyl groups substituted with a cyclic alkyl group which may contain a hetero atom in the ring, which are represented by C or E in the above general formula (1-1) may contain, if necessary, a hetero atom in the chain thereof. The hetero atoms include, for example, oxygen, nitrogen and sulfur atoms. The groups containing such a hetero atom in the chain include, for example, hydroxyethoxymethyl group, methoxymethyl group, methoxyethyl group, chloroethoxymethyl group, aminoethoxymethyl group, monomethylaminoethoxymethyl group, dimethylaminoethoxymethyl group, azidoethoxymethyl group, methylthioethyl group, phenylethoxymethyl group, 2-pyridylethoxymethyl group, 3-pyridylethoxymethyl group, 4-pyridylethoxymethyl group, cyclohexylethoxymethyl group and piperidine-1-ylethoxymethyl group.
C and E in the general formula (1-1) are each preferably a lower alkyl group, a substituted or unsubstituted amino-lower alkyl group or a lower alkyl group substituted with a cyclic alkyl group (containing or not containing a hetero atom in the ring), and they may contain a hetero atom in the chain thereof. More preferably, they are each an aryl-lower alkyl group or a lower alkyl group substituted with a cyclic alkyl group (containing or not containing a hetero atom in the ring), and they may contain a hetero atom in the chain thereof. Preferred examples of them include methyl group, methoxymethyl group, aminoethoxymethyl group, dimethylaminoethoxymethyl group, phenylethoxymethyl group, cyclohexylethoxymethyl group and piperidine-1-ylethoxymethyl group. Among them, methyl group, methoxymethyl group, aminoethoxymethyl group, phenylethoxymethyl group and cyclohexylethoxymethyl group are more preferred.
D in the above general formulae (1) and (1-1) is preferably hydrogen atom.
F in the above general formulae (1) and (1-1) preferably represents a group of the following general formula (15), thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group, pyridine-2-yl group, cyclohexyl group, morpholine-4-yl group, imidazole-1-yl group or pyrrolidinone-1-yl group.
F more preferably represents a group of the general formula (15) or morpholine-4-yl group. Those represented by the general formula (15) such as phenyl group are particularly preferred. 
wherein R13, R14, R15, R16 and R17 may be the same or different from each other and each represent hydrogen atom, a halogen atom, hydroxyl group, carboxyl group, amino group, cyano group, nitro group, a lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a lower alkynyl group, a lower alkylamino group, a lower alkylthio group, a lower alkanoyl group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an aryl-lower alkyl group, an aryl-lower alkoxyl group, a lower alkoxycarbonyl group, carbamoyl group which may have a substituent, a carboxyamido group which may have a substituent, an aroyl group, an aryl group, a heteroaryl group or a saturated cyclic hydrocarbon group having 3 to 8 carbon atoms, they may contain a hetero atom in the chains thereof, and two of R13 to R15 may be bonded together to form a ring.
Thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group, pyridine-2-yl group and cyclohexyl group may be either unsubstituted or substituted. When they contain two or more substituents, these substituents may together form a ring. The substituents are those listed above with reference to R1 to R5. The rings formed by them together are those listed above with reference to group A.
G is preferably hydrogen atom.
X1 is preferably an interatomic bond.
The groups represented by Y are preferably those of general formulae (6), (7), (8)-1, (8)-2 and (8)-3 wherein R9 and R10 each represent hydrogen atom and R0 represents phenyl group. When R0 and F in Y are condensed to form a ring, the ring is a tricyclic group such as fluorene, dihydroanthracene, xanthene, thioxanthene, dihydroacridine or dibenzosuberane.
In the present invention, it is preferred that Y in the general formula (1) represents a group of the general formula (6).
Y in the general formula (1) preferably represents a group of any of general formulae (7), (8)-1, (8)-2 and (8)-3.
In general formula (1), C is preferably a substituted or unsubstituted amino-lower alkyl group wherein the substituent represents hydrogen atom or a lower alkyl group and it may contain a hetero atom in the chain thereof, an azido-lower alkyl group, an aryl group, a heteroaryl group, an aryl-lower alkyl group, a heteroaryl-lower alkyl groups or a lower alkyl group substituted with a cyclic alkyl group which may contain a hetero atom in the ring thereof. C is preferably a lower alkyl group.
In general formula (1), E is preferably a substituted or unsubstituted amino-lower alkyl group wherein the substituent represents hydrogen atom or a lower alkyl group and it may contain a hetero atom in the chain thereof, an azido-lower alkyl group, an aryl group, a heteroaryl group, an aryl-lower alkyl group wherein the alkyl group may contain a hetero atom, a heteroaryl-lower alkyl group wherein the alkyl group may contain a hetero atom, or a lower alkyl group (containing or not containing a hetero atom) substituted with a cyclic alkyl group which may contain a hetero atom in the group thereof. E is preferably a lower alkyl group.
It is preferred that in general formula (1), D represents hydrogen atom, G represents hydrogen atom, X1 represents an interatomic bond and Y represents a group of general formula (6) wherein R9 and R10 each represent hydrogen atom.
It is also preferred that in general formula (1), D represents hydrogen atom, G represents hydrogen atom, X1 represents an interatomic bond and Y represents a group of any of general formulae (7), (8)-1, (8)-2 and (8)-3.
It is further preferred that in general formula (1), B represents a group of general formula (3), a group of general formula (4) wherein either R7 or R8 represents hydrogen atom or B and C are condensed together to form a lactone ring, D represents hydrogen atom, G represents hydrogen atom, X1 represents an interatomic bond and Y represents a group of general formula (6) wherein R9 and R10 each represent hydrogen atom, a group of general formula (7) or a group of general formula (8)-1, (8)-2 or (8)-3.
It is also preferred that in general formula (1), B represents a group of general formula (3), wherein R6 represents hydrogen group, or a group of general formula (4) wherein either R7 or R8 represents hydrogen atom, D represents hydrogen atom, G represents hydrogen atom, X1 represents an interatomic bond and Y represents a group of general formula (6) wherein R9 and R10 each represent hydrogen atom, a group of general formula (7) or a group of general formula (8)-1, (8)-2 or (8)-3.
It is preferred that in general formula (1), B represents a group of general formula (3), wherein R6 represents hydrogen group, D represents hydrogen atom, G represents hydrogen atom, X1 represents an interatomic bond and Y represents a group of general formula (6) wherein R9 and R10 each represent hydrogen atom, a group of general formula (7) or a group of general formula (8)-1, (8)-2 or (8)-3.
It is preferred that in general formula (1), B represents a group of general formula (3), C represents any of substituted or unsubstituted amino-lower alkyl groups, wherein the substituent represents hydrogen atom or a lower alkyl group and, if necessary, the chain may contain a hetero atom, an azido-lower alkyl group, an aryl group, a heteroaryl group, an aryl-lower alkyl group, a heteroaryl-lower alkyl group, wherein the alkyl group may contain a hetero atom, a lower alkyl group substituted with a cyclic alkyl group which may contain a hetero atom, D represents hydrogen atom, G represents hydrogen atom and X1 represents an interatomic bond. C preferably represents a lower alkyl group.
It is preferred that in general formula (1), B represents a group of general formula (3), D represents hydrogen atom, E represents any of substituted or unsubstituted amino-lower alkyl groups, wherein the substituent represents hydrogen atom or a lower alkyl group and, if necessary, the chain may contain a hetero atom, an azido-lower alkyl group, an aryl group, a heteroaryl group, an aryl-lower alkyl group, a heteroaryl-lower alkyl group, a lower alkyl group substituted with a cyclic alkyl group which may contain a hetero atom, G represents hydrogen atom, X1 represents an interatomic bond. E preferably represents a lower alkyl group.
It is preferred that in general formula (1), B represents a group of general formula (3) wherein R6 represents hydrogen atom, C represents an aryl-lower alkyl group, a heteroaryl-lower alkyl group, a lower alkyl group substituted with a cyclic alkyl group which may contain a hetero atom, D represents hydrogen atom, G represents hydrogen atom, X1 represents an interatomic bond. C also preferably represents a lower alkyl group.
It is preferred that in general formula (1), B represents a group of general formula (3) wherein R6 represents hydrogen atom, D represents hydrogen atom, E represents an aryl-lower alkyl group, a heteroaryl-lower alkyl group, a lower alkyl group substituted with a cyclic alkyl group which may contain a hetero atom, G represents hydrogen atom, X1 represents an interatomic bond. E also preferably represents a lower alkyl group.
Preferred are dihydropyridine derivatives of the general formula (1) wherein A represents a group of the general formula (2), B represents a group of the general formula (3), wherein R6 represents hydrogen atom, D represents hydrogen atom, F represents a group of the general formula (15), G represents hydrogen atom, X1 represents an interatomic bond, Y represents a group of general formula (6) wherein R9 and R10 each represent hydrogen atom, a group of general formula (7) or a group of general formula (8)-1, (8)-2 or (8)-3 and pharmaceutically acceptable salts thereof.
Dihydropyridine derivatives (1) of the present invention can be produced by processes described below:
For example, dihydropyridine derivatives (1-2) wherein B represents carboxyl group [R6 in general formula (3) represents hydrogen atom] and D represents hydrogen atom can be produced by the following reaction scheme: 
Namely, dihydropyridine derivatives (1-2) of the present invention can be produced by converting a dihydropyridine diester derivative (16) into compound (17) by, for example, catalytic reduction, condensing the obtained product with an amine (18), and treating the condensation product with a base such as sodium hydroxide.
Dihydropyridine diester derivatives (16) used in the above-described process can be produced as follows: 
Namely, dihydropyridine diester derivatives (16) are obtained by reacting an aldehyde (20), a 2-cyanoethyl acylacetate (21) and an 3-aminocrotonic acid ester derivative (22). Dihydropyridine diester derivatives (16) are obtained by reacting an aldehyde (20), 2-cyanoethyl 3-aminocrotonate derivative (23) and a benzyl acylacetate (24).
Dihydropyridine diester derivatives (16) can be produced also by the following process: 
Namely, a compound (25) is obtained by Knoevenagel reaction of an aldehyde (20) and a benzyl acylacetate (24). Then the compound (25) is reacted with an 2-cyanoethyl 3-amino-crotonate derivative (23) to obtain a dihydropyridine diester derivative (16). In another process, a compound (26) obtained by Knoevenagel reaction of an aldehyde (20) and a 2-cyanoethyl acylacetate (21) is reacted with a benzyl 3-aminocrotonate derivative (22) to obtain a dihydropyridine diester derivative (16).
The dihydropyridine derivatives (1-2) can be produced also by the following reaction scheme: 
Namely, a dihydropyridine diester derivative (27) is converted into a compound (28) by treating it with a base such as sodium hydroxide, and the compound (28) is condensed with an amine (18) to obtain an amide derivative (29). This product (29) is converted into the dihydropyridine derivative (1-2) of the present invention by, for example, the catalytic reduction.
The dihydropyridine diester derivative (27) used in the above-described process can be produced by the same process as that employed for the production of the dihydropyridine diester derivative (16).
The dihydropyridine derivatives (1-2) can be produced as follows: 
Namely, a compound (32) is obtained by subjecting an aldehyde (20) and an acylacetic acid amide derivative (30) to Knoevenagel reaction, and reacting the obtained compound (31) with a 2-cyanoethyl 3-aminocrotonate derivative (23) to obtain a compound (32). This product is treated with a base such as sodium hydroxide to obtain a dihydropyridine derivative (1-2) of the present invention. The compound (32) can be obtained also by directly reacting the aldehyde (20), the acylacetic acid amide derivative (30) and the 2-cyanoethyl 3-aminocrotonate derivative (23).
Dihydropyridine derivatives (1-3) of the above formula wherein B represents an ester group [R6 in general formula (3) represents a substituent excluding hydrogen atom] and D represents hydrogen atom can be produced as follows: 
Namely, the dihydropyridine derivatives (1-3) of the present invention can be produced by condensing the dihydropyridine derivative (1-2), synthesized by the process described above, with an alcohol (33).
Dihydropyridine derivatives (1-4) of the above formula wherein B represents a substituted carbamoyl group of general formula (4) and D represents hydrogen atom can be produced as follows: 
Namely, the dihydropyridine derivatives (1-4) of the present invention can be produced by condensing the dihydropyridine derivative (1-2), synthesized by the process described above, with a substituted amine (34).
Dihydropyridine derivatives (1-5) of the above formula wherein B represents cyano group and D represents hydrogen atom can be produced as follows: 
Namely, the dihydropyridine derivatives (1-5) of the present invention can be produced by reacting a compound (31), obtained by Knoevenagel reaction of the aldehyde (20) and an acylacetic acid amide derivative (30), with a 3-aminocrotonitrile derivative (35).
Dihydropyridine derivatives (1) containing an amine as the substituent of C or E can be obtained by using a halogen atom-containing compound, carrying out the reaction steps, converting the halogen atom-containing product into an azide with sodium azide or the like in the final step or the step preceding to the final step and reducing the obtained product into a primary amino group-containing derivative thereby by the hydrogenation or the like. The dihydropyridine derivatives (1) containing an amine as the substituent of C or E can be also obtained by reacting the halogen atom with a corresponding amine.
Benzyl acylacetates (24) used as the starting material can be produced as follows: 
Namely, benzyl acylacetates (24) can be obtained by reacting Meldrum""s acid (36) with an acyl chloride (37) in the presence of a proper base to obtain a compound (38) and then reacting the obtained compound (38) with benzyl alcohol (39).
Benzyl acylacetates (24) can also be produced as follows: 
Namely, benzyl acylacetates (24) can be obtained by the transesterification of a methyl acylacetate (40) and benzyl alcohol (39).
Optical isomers of 1,4-dihydropyridines represented by general formula (1) or (1-1) are possible because they have an asymmetric carbon atom. The compounds of the present invention also include those optical isomers.
When the compounds of general formula (1) can form salts thereof, the salts are pharmaceutically acceptable ones such as ammonium salts, salts thereof with alkali metals, e.g. sodium and potassium, salts thereof with alkaline earth metals, e.g. calcium and magnesium, salts thereof with aluminum and zinc, salts thereof with organic amines, e.g. morpholine and piperidine, and salts thereof with basic amino acids, e.g. arginine and lysine.
The compounds of general formula (1) and salts thereof are administered as they are or in the form of various medicinal compositions to patients. The dosage forms of the medicinal compositions are, for example, tablets, powders, pills, granules, capsules, suppositories, solutions, sugar-coated tablets and depots. They can be prepared with ordinary preparation assistants by an ordinary method.
For example, the tablets are prepared by mixing the dihydropyridine derivative, the active ingredient of the present invention, with any of known adjuvants such as inert diluents, e.g. lactose, calcium carbonate and calcium phosphate; binders, e.g. acacia, corn starch and gelatin; extending agents, e.g. alginic acid, corn starch and pre-gelatinized starch; sweetening agents, e.g. sucrose, lactose and saccharin; corrigents, e.g. peppermint, and cherry; and lubricants, e.g. magnesium stearate, talc and carboxymethyl cellulose.
The N-type calcium channel inhibitor containing one of the compounds of above general formula (1-1) or one of salts thereof as active ingredient is usable as a therapeutic agent for various diseases, for example, acute stage of ischemic cerebrovascular disorders caused by cerebral infarction or intracerebral bleeding (including subarachnoidal hemorrhage); progressive neurodegenerative diseases such as Alzheimer""s disease, AIDS related dementia and Parkinson""s disease, dementia due to cerebrovascular disorder and ALS; neuropathy caused by head injury; various pains such as pain caused by spinal injury, diabetes or thromboangiitis obliterans, postoperative pain, migraine and visceral pain; various diseases associated with psychogenic stress such as bronchial asthma, unstable angina and irritable colitis; emotional disorder withdrawal symptoms after addiction to drugs such as ethanol addiction withdrawal symptoms.
The dose of the compound of general formula (1) or salt thereof used for the above-described purpose varies depending on the intended therapeutic effect, administration method, period of the treatment, and age and body weight of the patient. The dose is usually 1 xcexcg to 5 g a day for adults in the oral administration, and 0.01 xcexcg to 1 g a day for adults in the parenteral administration.
The following Examples will further illustrate the present invention, which are only preferred embodiments of the invention and which by no means limit the invention.